tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate | 170282-45-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate
• 英文别名: tert-butyl (4R)-4-hydroxy-4-(2-methylphenyl)butanoate
• CAS: 170282-45-8
• 化学式: C₁₅H₂₂O₃
• 分子量: 250.338
• InChiKey: GDNXDLQAOGCMDD-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate 在 sodium hydroxide 、 sodium hydride 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 24.0h， 生成 (R)-4-[5-(Benzo[1,3]dioxol-5-ylmethoxy)-2-cyano-phenoxy]-4-o-tolyl-butyric acid
  参考文献：
  名称：

  Selective Endothelin A Receptor Antagonists. 3. Discovery and Structure−Activity Relationships of a Series of 4-Phenoxybutanoic Acid Derivatives

  摘要：

  The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

  DOI：

  10.1021/jm9707131
• 作为产物：
  描述：

  4-(2-甲基苯基)-4-氧代丁酸 在 硫酸 、 二乙醇胺 、 (+)-二异松蒎基氯硼烷 、 叔丁醇 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 反应 56.0h， 生成 tert-butyl (R)-4-hydroxy-4-(2-methylphenyl)butanoate
  参考文献：
  名称：

  Selective Endothelin A Receptor Antagonists. 3. Discovery and Structure−Activity Relationships of a Series of 4-Phenoxybutanoic Acid Derivatives

  摘要：

  The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.

  DOI：

  10.1021/jm9707131

文献信息

• Substituted phenyl compounds
  申请人：Rhone-Poulenc Rorer Limited

  公开号：US06211234B1

  公开（公告）日：2001-04-03

  Compounds of formula (I) are described wherein R1 is hydrogen, -(lower alkyl)q(CO2R6 or OH), —CN, —C(R7)═NOR8, NO2, —O(lower alkyl)R9, —C≡C—R10, —CR11═C(R12)(R13), —C(═O)CH2C(═O)CO2H, —CO(R14), alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, thiocarbamoyl, substituted carbamoyl, substituted thiocarbamoyl, sulphamoyl or an optionally substituted nitrogen-containing ring, m, n, o and p are independently zero or 1 and R2, R3, R4 and R5 are various groups; and physiologically acceptable salts, N-oxides and prodrugs thereof. The compounds have endothelin antagonist activity and are useful as pharmaceuticals.

  式(I)的化合物描述如下，其中R1为氢，-(较低烷基)q(CO2R6或OH)，—CN，—C(R7)HNOR8，NO2，—O(较低烷基)R9，—C≡C—R10，—CR11CH(R12)(R13)，—C(O)CH2C(O)CO2H，—CO(R14)，烷基硫醚，烷基亚砜基，烷基磺酰基，氨基甲酰基，硫代氨基甲酰基，取代的氨基甲酰基，取代的硫代氨基甲酰基，磺酰胺基或可选择取代的含氮环，m、n、o和p独立地为零或1，R2、R3、R4和R5为各种基团；以及其生理学上可接受的盐、N-氧化物和前药。这些化合物具有内皮素拮抗活性，并可用作药物。
• Selective Endothelin A Receptor Antagonists. 3. Discovery and Structure−Activity Relationships of a Series of 4-Phenoxybutanoic Acid Derivatives
  作者：Peter C. Astles、Clive Brealey、Thomas J. Brown、Vincenzo Facchini、Caroline Handscombe、Neil V. Harris、Clive McCarthy、Iain M. McLay、Barry Porter、Alan G. Roach、Carol Sargent、Christopher Smith、Roger J. A. Walsh

  DOI：10.1021/jm9707131

  日期：1998.7.1

  The third in this series of papers describes our further progress into the discovery of a potent and selective endothelin A (ETA) receptor antagonist for the potential treatment of diseases in which a pathophysiological role for endothelin has been implicated. These include hypertension, ischemic diseases, and atherosclerosis. In earlier publications we have outlined the discovery and structure-activity relations of two moderately potent series of nonpeptide ETA receptor antagonists. In this paper, we describe how a pharmacophore model for ETA receptor binding was developed which enabled these two series of compounds to be merged into a single class of 4-phenoxybutanoic acid derivatives. The subsequent optimization of in vitro activity against the ETA receptor led to the discovery of (R)-4-[2-cyano-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (12m). This compound exhibits low-nanomolar binding to the ETA receptor and a greater than 1000-fold selectivity over the ETB receptor. Data are presented to demonstrate that 12m is orally bioavailable in the rat and is a functional antagonist in vitro and in vivo of ET-1-induced vasoconstriction.